Ablative AIIogeneic transplantation is used to treat diseases, though the potential severe toxicitiesof the procedure have precluded its broad use for adults with severe effects from sickle cell disease. The long-term objectives of this project are to reduce the toxicity and improve the overall survival following non-myeloablative allogeneic transplantation for sickle cell disease. The central hypothesis of this project is that allogeneic stem cells infused after a less toxic, non- myeloablative regimen will induce a stable donor hematopoietic state. Two complementary strategies will be pursued in order to test this hypothesis. First, persons with severe illness from sickle cell disease will be transplanted with HLA matched sibling donor peripheral blood stem cells (PBSC) using a less toxic non-myeloablative regimen. The primary purpose of this clinical trial is to assess the feasibility in terms of toxicity and engraftment of a less toxic, nonablative conditioning regimen of in vivo alemtuzumab (anti-CD52) monoclonal antibody, moderate dose fludarabine, and cyclophosphamide for patients with sickle cell disease. Early stoppping rules for toxicity and failure of donor engraftment are an important part of the IRB approved trial. Clinical outcomes, quality of life, and cost efficiency of the nonmyeloablative transplant will be evaluated. Secondary purposes of this study are to investigate recipient immune reconstitution to ensure a robust recovery of immune function in these patients with sickle cell disease. The second approach will rely on in vitro measurements to define the kinetics of immune reconstitution in transplant recipients. These measurements will consist of general, antigen specific, and alloreactive immune responses to define the dynamics of immune reconstitution following allogeneic transplantation in this patient population. Results of these investigtions will lead to future trials of efficacy of this approach with adults with severe sickle cell disease and ensure recovery of a strong immune system such that we do not simply trade one illness (sickle cell disease) for another (chronic immunosuppression).